The human mitochondrial DNA (mtDNA) encodes many gene products which are essential for oxidative phosphorylation (OXPHOS), the process by which cellular energy is produced via aerobic respiration. Mutations found in the mtDNA therefore frequently result in OXPHOS defects, tissue dysfunctions, and, ulitmately, disease. More that 70 point mutations and greater than 200 rearrangements in the mtDNA have been associated with human disease ranging from lethal, pediatric disorders to late-onset, neurodegenerative disease. Despite the central position of the mitochondria in metabolism and the clinical relevance of mitochondrial dysfunction, bioenergetic disease has been remarkable understudied in Russia. In an effort to nucleate such study, we propose to investigate the spectrum and frequency of mitchondrial disease in Siberia. To do so, we propose three specific aims. First, we will identify and verify patients/families with mitochondrial disease, using the extensive and thorough clinical records available in the major hospitals in the largest cities of southwestern and south-central Siberia, the most populous region of Siberia. We will focus on those clinical signs which are most common in maternally inherited disease, including optic atrophy/blindness, sensorineural deafness, myopathy, basal ganglia disease, and diabetes. Second, we will screen the Siberian families for the presence of 20 known, pathogenic mtDNA mutations and determine the mtDNA genetic background for those families found to harbor a mutation. Third, for those families which do not contain a known mutation, we will completely sequence the mtDNA to find new, disease causing variants. The long term goals of this project include: (1) to understand the frequency and spectrum of mitchondrial disease in Siberia/Russia, (2) to provide the foundation for biochemical analysis as well as the study of complex genetic mechanisms in OXPHOS disease, both of which will help to elucidate the underlying pathophysiological basis for this class of diseases, (3) to permit our Russian contingent to become a self-sufficient laboratory for the study of clinical mitochondrial genetics, and (4) to increase the awareness of mitochondrial disease in the Russian medical scientist communities.